CAREER: Developing a Computational Workflow to Quantify Atomic-level Allosteric Mechanisms

职业：开发计算工作流程来量化原子级变构机制

• 批准号: 2238706
• 负责人: Martin McCullagh
• 金额: $ 56.98万
• 依托单位: Oklahoma State University
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-05-01 至 2028-04-30
• 项目状态: 未结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=2238706&HistoricalAwards=false
• 关键词: CAREER; Developing; Computational; Workflow; Quantify

With support from the Chemical Theory, Models and Computational Methods program in the Division of Chemistry, and the Established Program to Stimulate Competitive Research (EPSCoR), Martin McCullagh and his research group at Oklahoma State University will develop computational methods and workflows to quantify allosteric response in proteins. Allostery in proteins can switch on and off the primary function through the binding of a molecule at a secondary site on the protein. This behavior serves as important handle for the development of therapeutics as well as the design of novel proteins. The computational workflows developed in the McCullagh group will be used to quantify allosteric response as well as identify new allosteric sites for further regulation of the protein. The McCullagh group will also develop jupyter notebook-based chemistry lessons to both introduce chemistry concepts in a novel way and introduce aspects of coding to undergraduate chemistry students.The McCullagh group will develop and verify a computational workflow to quantify allosteric response and describe the atomic-level details that underlie this behavior. Allostery is the altering of enzyme function at one site due to a perturbation of the enzyme at a distal site. Despite over a century of work on this topic, two key questions remain unanswered: (1) What are the atomic-level changes that contribute to allostery in a complete four-state thermodynamic cycle? (2) Can we harness the atomic-level allosteric mechanisms to identify new targets to impact the observed allostery? This project will address these questions using two pyruvate kinase isozymes as model systems. The K-type allosteric response of these enzymes is a pivotal control valve for the last step in glycolysis. This project will also develop and freely distribute online jupyter notebook-based chemistry lessons.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

在化学系的化学理论、模型和计算方法项目以及刺激竞争性研究的既定项目（EPSCoR）的支持下，俄克拉荷马州州立大学的Martin McCullagh和他的研究小组将开发计算方法和工作流程，以量化蛋白质中的变构反应。 蛋白质中的变构性可以通过在蛋白质上的次级位点结合分子来开启和关闭主要功能。 这种行为是开发治疗药物以及设计新蛋白质的重要手段。 McCullagh小组开发的计算工作流程将用于量化变构反应，并确定新的变构位点以进一步调节蛋白质。 McCullagh小组还将开发基于jupyter笔记本的化学课程，以新颖的方式介绍化学概念，并向本科化学学生介绍编码方面。McCullagh小组将开发和验证计算工作流程，以量化变构反应并描述这种行为背后的原子级细节。变构是由于酶在远端位点的扰动而导致酶在一个位点的功能改变。尽管在这一课题上的工作已经进行了世纪，但有两个关键问题仍然没有得到解答：（1）在一个完整的四态热力学循环中，什么是原子水平的变化？(2)我们能否利用原子水平的变构机制来识别新的靶点来影响观察到的变构？ 本计画将以两种丙酮酸激酶同功酶为模式系统来探讨这些问题。 这些酶的K型变构反应是糖酵解最后一步的关键控制阀。 该项目还将开发和免费分发在线jupyter笔记本为基础的化学课程。该奖项反映了NSF的法定使命，并已被认为值得通过使用基金会的智力价值和更广泛的影响审查标准进行评估的支持。